This is a renewal application for the Yale Center for Mendelian Genomics. The biology linking Mendelian mutations to traits has transformed our understanding of every organ system, identifying therapeutic targets, and allowing preclinical diagnosis and mitigation of disease risk. We know the consequence of mutation of fewer than 3,000 genes. With ~19,000 protein-coding genes, the vast majority of which are conserved across phylogeny, even allowing for 30% lethality, there are doubtless thousands of Mendelian loci awaiting discovery. The full utility of clinical sequencing will not be realized without bette understanding of the consequence of mutation of every gene. The advent of robust exome and genome sequencing allows unprecedented opportunity for discovery of new Mendelian trait loci. In the current cycle, by sequencing more than 7000 exomes from investigators world-wide we have identified 180 new Mendelian trait loci with high confidence, 35 phenotypic expansions, and hundreds more that are likely new trait loci across a range of traits and genetic mechanisms, including de novo mutations, incomplete penetrance, and complex rare recessive traits. Several new loci have immediate therapeutic implications. These results underscore that many new trait loci remain to be described and solved, motivating efforts to complete the human `knock out' map. We now propose, by building upon the current studies and through reduction in high quality exome cost to $330, to identify at least another 500 trait loci via the sequencing of more than 20,000 samples, advancing the understanding of genomes, health and disease.